chrX-50092130-C-T

Variant names:

• chrX-50092130-C-T
• rs797044814
• NM_001127898.4:c.2362C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001127898.4(CLCN5):​c.2362C>T​(p.Arg788*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: CLCN5 NM_001127898.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.05692
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 1.29
• Publications: 1 publications found

Genes affected

CLCN5 (HGNC:2023): (chloride voltage-gated channel 5) This gene encodes a member of the ClC family of chloride ion channels and ion transporters. The encoded protein is primarily localized to endosomal membranes and may function to facilitate albumin uptake by the renal proximal tubule. Mutations in this gene have been found in Dent disease and renal tubular disorders complicated by nephrolithiasis. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2013]

CLCN5 Gene-Disease associations (from GenCC):

• Dent disease type 1

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0363 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-50092130-C-T is Pathogenic according to our data. Variant chrX-50092130-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 208000.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127898.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN5	NM_001127898.4	MANE Select	c.2362C>T	p.Arg788*	stop_gained splice_region	Exon 15 of 15	NP_001121370.1
	CLCN5	NM_001440756.1		c.2374C>T	p.Arg792*	stop_gained splice_region	Exon 15 of 15	NP_001427685.1
	CLCN5	NM_001440757.1		c.2374C>T	p.Arg792*	stop_gained splice_region	Exon 15 of 15	NP_001427686.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN5	ENST00000376091.8	TSL:2 MANE Select	c.2362C>T	p.Arg788*	stop_gained splice_region	Exon 15 of 15	ENSP00000365259.3
	CLCN5	ENST00000307367.2	TSL:1	c.2152C>T	p.Arg718*	stop_gained splice_region	Exon 12 of 12	ENSP00000304257.2
	CLCN5	ENST00000376108.7	TSL:1	c.2152C>T	p.Arg718*	stop_gained splice_region	Exon 12 of 12	ENSP00000365276.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1079529 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 347577

African (AFR) AF: 0.00 AC: 0 AN: 26086

American (AMR) AF: 0.00 AC: 0 AN: 35165

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19257

East Asian (EAS) AF: 0.00 AC: 0 AN: 30102

South Asian (SAS) AF: 0.00 AC: 0 AN: 53700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4087

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 825382

Other (OTH) AF: 0.00 AC: 0 AN: 45488

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dent disease type 1 Pathogenic:1 Other:1

Apr 17, 2018

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This individual is hemizygous for a known nonsense variant, c.2362C>T, in the CLCN5 gene. This variant creates a premature stop codon (p.Arg788*). c.2362C>T (p.Arg788*) has not been listed in any population databases (i.e. ExAC, ESP or dbSNP). The variant has been reported in five unrelated patients with Dent's disease (Carballo-Trujillo et.al. Nephrol Dial Transplant 2003; 18(4): 717-723, Hoopes et.al. Kidney Int 2004; 65: 1615-1620, Wu et.al. Nephron Physiol 2009; 112: 53-62 & Grand et.al. Kidney Int 2009; 76: 999-1005). Segregation studies were performed by Carballo-Trujillo et.al and c.2362C>T was shown to cosegregate with the disease. In these reports, the variant is described as p.Arg718* (relative to transcript NM_000084.4). Functional studies in Xenopus laevis oocytes showed that this nonsense variant produced a truncated protein product and was lower in abundance in comparison to the wild-type. The truncation affected the cellular localisation of the protein (Grand et.al. Kidney Int 2009; 76: 999-1005). This variant is considered to be pathogenic according to the ACMG guidelines.

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

not provided Pathogenic:1

Apr 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg718*) in the CLCN5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the CLCN5 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Dent disease (PMID: 12637640, 31672324). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 208000). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CLCN5 function (PMID: 19657328). For these reasons, this variant has been classified as Pathogenic.

X-linked recessive nephrolithiasis with renal failure;C1839874:Proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis;C1845168:Hypophosphatemic rickets, X-linked recessive;C1848336:Dent disease type 1 Pathogenic:1

Oct 03, 2025

Rare Kidney Stone Consortium and the Mayo Clinic Hyperoxaluria Center, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG:PVS1, PM2, PP3, PP5

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	35
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		1.3
Vest4		0.54
GERP RS		3.5
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.057
dbscSNV1_RF	Benign	0.48
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs797044814; hg19: chrX-49856787; COSMIC: COSV56585339;